Identification of Chimeric Antigen Receptors That Mediate Constitutive or Inducible Proliferation of T Cells

Cancer Immunology Research - Tập 3 Số 4 - Trang 356-367 - 2015
Matthew J. Frigault1, Ji‐Hyun Lee1, Maria C. Basil1, Carmine Carpenito1, Shinichiro Motohashi2, John Scholler1, Omkar U. Kawalekar1, Sònia Guedan1, Shannon E. McGettigan1, Avery D. Posey1, Sonny Ang3, Laurence J.N. Cooper3, Jesse M. Platt1, F. Brad Johnson1, Chrystal M. Paulos4,5, Yangbing Zhao1, Michael Kalos1, Michael C. Milone1, Carl H. June1
11Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
22Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
33Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas.
44Department of Microbiology and Immunology, Hollings Cancer Center at the Medical University of South Carolina, Charleston, South Carolina.
55Department of Surgery, Hollings Cancer Center at the Medical University of South Carolina, Charleston, South Carolina.

Tóm tắt

AbstractThis study compared second-generation chimeric antigen receptors (CAR) encoding signaling domains composed of CD28, ICOS, and 4-1BB (TNFRSF9). Here, we report that certain CARs endow T cells with the ability to undergo long-term autonomous proliferation. Transduction of primary human T cells with lentiviral vectors encoding some of the CARs resulted in sustained proliferation for up to 3 months following a single stimulation through the T-cell receptor (TCR). Sustained numeric expansion was independent of cognate antigen and did not require the addition of exogenous cytokines or feeder cells after a single stimulation of the TCR and CD28. Results from gene array and functional assays linked sustained cytokine secretion and expression of T-bet (TBX21), EOMES, and GATA-3 to the effect. Sustained expression of the endogenous IL2 locus has not been reported in primary T cells. Sustained proliferation was dependent on CAR structure and high expression, the latter of which was necessary but not sufficient. The mechanism involves constitutive signaling through NF-κB, AKT, ERK, and NFAT. The propagated CAR T cells retained a diverse TCR repertoire, and cellular transformation was not observed. The CARs with a constitutive growth phenotype displayed inferior antitumor effects and engraftment in vivo. Therefore, the design of CARs that have a nonconstitutive growth phenotype may be a strategy to improve efficacy and engraftment of CAR T cells. The identification of CARs that confer constitutive or nonconstitutive growth patterns may explain observations that CAR T cells have differential survival patterns in clinical trials. Cancer Immunol Res; 3(4); 356–67. ©2015 AACR.

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Cancer Immunology Research

Tập 3 Số 4

356-367

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